Synthes Award for Resident Research on Spinal Cord and Spinal Column Injury: granulocyte macrophage colony stimulating factor (GM-CSF) prevents apoptosis and improves functional outcome in experimental spinal cord contusion injury.

OBJECTIVE: Granulocyte macrophage colony stimulating factor (GM-CSF) is a potent hematopoietic cytokine, which stimulates stem cell proliferation in the bone marrow and inhibits apoptotic cell death in leukocytes. However, the effects of GM-CSF in the central nervous system are still unclear. The present study was undertaken to determine if GM-CSF can rescue neuronal cells from apoptosis and improve neurologic function in a spinal cord injury (SCI) model. METHODS: To study the effect of GM-CSF on apoptotic neuronal death, we used a staurosporine-induced neuronal death model in a Neuro 2A (N2A) cell line (in vitro) and in a rat SCI model (in vivo). N2A cells were preincubated with GM-CSF for 60 minutes before being exposed to staurosporine for 24 hours. To inhibit GM-CSF, we pretreated N2A cells with antibodies of the GM-CSF receptor for 60 minutes. SCI was made by clip compression. Rats were treated with daily GM-CSF (20 microg/d) for 5 days. The number of apoptotic cells in the spinal cord and neurologic improvements were checked. RESULTS: GM-CSF pretreatment was found to significantly protect N2A cells from apoptosis, and neutralizing antibodies for the GM-CSF receptors inhibited the rescuing effect of GM-CSF on apoptosis. In the rat SCI model, neurologic functions improved significantly in the GM-CSF-administered group versus the phosphate buffered saline (PBS)-treated control. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeled) staining showed that GM-CSF administration reduced apoptosis in the injured spinal cord. CONCLUSION: Treatment of SCI with GM-CSF showed some beneficial effects. Neuronal protection against apoptosis is viewed as a likely mechanism underlying the therapeutic effect of GM-CSF in SCI.